Chemical compounds and process of preparing the same



Patented Dec. 27, 1949 2,492,193

CHEMICAL dOMPOUNDS AND PROCESS OF PREPARING THE SM Lewis H. Sarett,Princeton, N. J. asslgnor to Merck & 00., Inc., Railway, N. 1., acorpora-. tion of New Jersey i No Drawins. Original application July 14,1945, Serial No. 605,194. Divided and this appllca tion February23,1946, Serial No. 649,765

1 6 Claims. (CL ZOO-397.4) z This invention is concerned generally withI structural formulae the former configuration is novel chemicalcompounds of the cyclopentanoshown by writing the -17 substituent(hydroxyl) dimethylpolyhydrophenanthrene series and to to the right ofthe 0-1! carbon side chain, thus processes of preparing same; moreparticularly it 3mg]; 1 relates to novel compounds useful as interme- 5Hon diates in the synthesis of the adrenal cortical Q hormoneA4,5-3,1l,20-'triketo-17(p), 21-hydroxy pregnene. This application is adivisional of copending application Serial No. 605,194, filed in t 1 m,m above t m h in, thug July 14, 1945, now abandoned. OH

This hormone is known to occur naturally in cn=cm the adrenal cortex; ithas the structural formula: X

memoir =0 3. The stereochemical relationship of rings A 0 1g, g g 0H l5andBisindicatedinthe formulae byasolid line representin: the valencebond in the cis confiscf 5 inch, uration. L c 14 D In accordance withthe present invention it is cm 9H\ 11-- m now found this hormone can besynthesized by f f I 20 reactionsindicatedasioiiows:

A B CHO CHI {a} 5} err-coin err-coin H H: (Standard numbering ofC-posltions.) This formula, for purposes of convenience, is cahereinafter reproduced below in the abbreviated form:

CHIOH so =0 H no CHil OH I aoyl-halldo- I liormln on mm err-coir In thefoliowinedescription of the invention. the stereochemical relationshipsof substituents cm are indicated by the following conventions:

" 1. A substituent at the 0-3 position which is trans to the 0-10 methylgroup is parenthetically d signated (a). no

-2. A substituent at the 0-17 position, the

stereochemical configuration of which is identical with that of thenaturally occurring adrenal hormones, is parenthetically designated (p);the

epimeric configuration is designated (a). In the if 1 l 7 o 0 com OH.CHI CH 10 CH: cm

VII B0 B0 CHI 4 H H J m X! CH; cm o r lnczcn oil-NH, on.

0H on CH CECE cm! cn=cm R0 o w CH: v1

-0 HONO H1,

141,0 0H; catalyst HOB. 80 0 H OH; H

CH: 3 lmlating agent cmx' H 011 CH CH1] OH=CH1 CH: CH

CH; halogenating 818! H 9 R R'O cm I on H r H Q\ xv: xv

CH: B0 cH-cmx' CH-CHiOR" CH OH on MOB." OH H L m w xvn m H $223 we webyde- CH hydrolysis emnpodtion o cn-cmon'" cH-cmoH CH: CH: 8 R'"0Hor(RIII),O

CH CH: 1 X

xvm XIX oxidation 3 H hydrolyfls 1 oxidation cn-cmon on-cmon CH: CH

hydrol- CH: ysis CH XXI XX v acylati iz agen H H CHaOH HOH CH-CHgOB' onOK on I: droxysting 0 men CH CH XXII XXIII acylating agent CH'O RIIIIIRI!!! Ho RIIIII RI!!! 011. /0H on, on

---s CH: X" CHI XXV XXIV H II CHO RI!!! RII-III HORN!!! CHORIIIII CH; OHCH OH -a CH: pyridine CH:

a x H i V XXVI XXV lhydrolysis CHOR CHOH HOH H-OH on, on on, on

QB; (R010 CE:

XXVIII XXVII loxidation CHQOR.

OH; OH CH OH: CHI

XXIX (XX lhydrelysis QFHnDH OH: OH

| O I on, i

In the above formulae, R, R, R", R', R

RP, and R are acyl; X, X and X" are halogen; and M is an alkali metal oran alkaline earth metal /2.

The reactions above indicated are conducted as follows:

3-hydroxy-ll-keto-bisnorcholanic acid (I) is acylated producing3-acyloxy-ll-keto-bisnorcholanic acid (11) which is treated with anagent capable of converting an organic carboxylic acid to thecorresponding acid halide, thus forming the acid halide of3-acyloxy-l1-keto-bisnorcholanic acid (III). Upon treatment of this acidhalide with an alkali metal azide or alkaline earth metal azide, theazide of 3-acyloxy-11-ketobisnorcholanic acid (IV) is formed.Decomposion of this azide with an acidic aqueous solution produces3-acyloxy-11-keto-20-aminopregnane (V).

Upon treatment of this compound (V) with nitrous acid, a mixturecontaining predominantly A -3-acy1oxy-1l-keto-pregnene (VI) and A3-acyloxy-ll-keto-pregnene (VII) and a minor amount of3-acyloxy-11-keto-20-hydroxypregnane (VIII) results. The proportion ofthe desired compound (VI) present in this mixture can be increased bytreating the mixture with an aromatic sulfonyl halide followed byfurther treatment with a base to cause removal of the elements of thecorresponding aromatic sulionic 11-keto-21-halo-pregnene (XVI) with analkali metal salt or alkaline earth metal droxy-ll-ketopregnene (XV),and this compound is halogenated to produce A -ii-acyloxy- When treatedsalt of an organic acid, this compound yields A "--3,21-diacyloxy 11ketopregnene (XVII) which is hydrolyzed producing A "--3,21-dihydroxy-ll-ketopregnene (XVIII). The latter product (XVIII) ispartially esterified and the mono ester (XIX) thus produced is oxidizedto convert the unesterified hydroxy group in the 3 position to a ketogroup, thereby yielding the ester of A'=-3,l1-diketo-21-acyloxy-pregnene (XX). This product (XX) is hydrolyzedand the A"--3-,11-diketo 21 hydroxypregnene (XXI) thus formed isacylated producing A"-'-3,11-diketo-21-acyloxypregnene (XXII).Hydroxylation at the unsaturation oi the last mentioned compound (XXII)results in the production oi 3,11 diketo 17(3), 20,21-trihydroxypregnene(XXHI) which is then acylated to form 3,11-

dlketo-17 8) hydroxy-20,21 diacyloxypregnene (XXIV). When brominated,this compound yields 3,11-diketo-4-bromo-17 (p) -hydroxy-20,21-diacyloxypregnene (XXV). 1

This compound is then treated with a reagent capable of removing theelements of hydrogen bromide, thereby producing A*- -3,l1-diketo- 17(5)-hydroxy-20,2l-diacyloxypregnene (XXVI) which on hydrolysis forms A-3,11-diketo- 17(5) ,20,21-trihydroxypregnene ()QIVII) Partial acylationof this compound (XXVII) gives A -3,11-diketo-17(,8) ,20-dihydroxy2l-acyloxypregnene (XXVIII) which, when oxidized, yields a mixture of A-3,11,20-triketo-17(B) -hydroxyzl-acyloxypregnene (XXIX) and Ar-3,11,17- triketo androstene (XXX). Compounds (XXIX) and (XXX) may beseparated by conventional operations, for example chromotography, andcompound (XXIX) hydrolyzed to produce the desired adrenal hormone, A-3,l1,20-triketo- 17 (e) ,21-dihydroxypregnene.

This invention is concerned with compounds of the type represented byintermediates 20, 21 and 22 above, and with processes of producing inwhich Y is an oxidation-resistant group which can readily be convertedto a hydroxy group; and intermediates 21 and 22 may be represented bythe formula:

CHaOR CH: H

in which R is acyl or hydrogen.

v 8 The starting material employed in the process according to thisinvention, A"-'-3-hydroxy-11- keto-21-acyloxypregnene or the 3-acyloxyderivative thereof, may be obtained as described in copendingapplication Serial No. 649,764, filed February 23, 1946.

I In accordance, with this invention, an ester having the basicstructural formula:

CHaOY CH: AH

in which R is acyl or hydrogen and Y is an oxi dation-resistant groupwhich can readily be converted to a hydroxy group, for example, an acylgroup; is subjected to oxidation whereby the 3- substltuent is convertedto a keto group. The acyl group R above may be widely varied, forexample, it may be the acyl radical of acetic, propionic, butyric,valeric, caproic, capric, benzoic, toluic, or phenylacetic acid,of'which the lower aliphatic acids, 1. e. those having 6 carbon atoms orless, are preferred. The ester used as the starting material can beproduced by esterifying A -=-3,2l -dihydroxy-ll-ketopregnene with analiphatic or aromatic monobasic or dibasic acid or anhydride such assuccinic, phthalic, or benzoic acid, or succinic, acetic or phthalicanhydride. Preferably, a dibasic acid anhydride such as succinic acidanhydride is employed; when succinic acid anhydride is employed, thehemisuccinate (Y=CO.CH2.CH2.CO2H) is formed.

As the oxidizing agent chromium trioxide, chromic acid, a chromate saltin an acid medium or aluminum phenoxide in acetone can be used. Theoxidation should be carried out in dilute solution, e. g. 1 gram ofoxidizing agent per cc. of solution, at temperatures of the order of 15C., i. e. at or below usual room temperature, using a slight excess ofthe oxidizing agent above the stoichiometric amount required to oxidizethe substituent in the three position. Under the above reactionconditions, it is found that conversion to the keto compound occurs withhigh yields of the compound having the following structural formula:

CHQOY CH: 43H

Y being as above defined.

In further practice of this invention, this keto compound is saponifledto convert the 21 position substituent to a hydroxy group and then thiscompound is acylated, using an organic acid or acid anhydridehereinabove mentioned, preferably acetic anhydride, to give thecorresponding 9 21-acyloxy derivative having the structural formula:

In the following example, oxidation of the 21- hemisuccinate to convertthe 3-hydroxyl group to a keto group, followed by the saponiflcation andacetylation of the resultant keto compound is described, but it will beunderstood this example is only for purposes of illustration and thisinvention is not limited thereto.

Example A solution of 138 mg. of A -34a) -hydroxy-11-keto-21-hemisuccinoxypregnene in 14 cc. of glacial acetic acid at 12C. was treated dropwise with 65 mg. chromic acid in a mixture of 1.3 cc.of water and 1.3 cc. of glacial acetic acid. The temperature waspermitted to rise to 17 C. over a period of 45 minutes, the excesschromic acid was then destroyed with dilute sodium sulfite, the solutionconcentrated in vacuo, diluted with water and extracted with ether. Thewashed ethereal extract was concentrated to dryness pro-' ducing anon-crystalline residue consisting of A ""-3,11-diketo 21hemisuccinoxypregnene is about 80% yield.

The ester was then saponifled by heating with aqueous potassiumcarbonate on the steam bath. The neutral product so obtained was takenup in ether, washed, concentrated and crystallized from ethylacetate-pentane. A

' 3,1l-diketo-21-hydroxypregnene was obtained in practically 100% yield;it had a melting point of l50-151 C.

To a mixture of 5 cc. of pyridine and 5 cc. of acetic anhydride wasadded 845 mg. of the diketohydroxypregnene. -The solution was permittedto stand overnight and was then diluted with water.- The ethereal layerwas washed successively with dilute hydrochloric acid, dilute potassiumcarbonate and water, then concentrated to dryness on a steam bath givingabout 100% yield of A -3,11-diketo 21 acetoxypregnene as a colorlessglass.

While in the example the startin material used wasv a compound havingthe 3-hydroxy group in the trans form, a compound having this group inthe cis form also may be used as the steric configuration oi the groupin the 3 position is not important.

The temperatures mentioned in the example are room temperatures unlessotherwise indicated. The temperatures, however, are not critical and thereactions may be carried out at higher or lower temperatures; butextremely high temperatures should be avoided because of the likelihoodof decomposition of the desired products which may result from operationat such temperatures.

Unless otherwise stated, the reagents can be used in diil'erentproportions than are indicated in the above example, as the proportions,unless otherwise indicated, are not critical, although enough of thereagents should be employed to inin which Y is a lower aliphatic acylradical selected from the group consisting of monocarboxylic anddicarboxylic acid radicals, with a reagent selected from the groupconsisting of chromium trioxide, chromic acid, chromate salt in an acidmedium and aluminum phenoxide in acetone, to produce the corresponding3-keto compound, saponitying this compound, and then acylating theproduct to obtain the corresponding A "#-3,1l-diketo-21-lower aliphaticacyloxy com pound.

hydrOXY-II-keto-ZI-hemisuccinoxypregnene with 5. The process thatcomprises oxidizing a compound of the basiciormula:

CHsOY OH! I H CHsOH CHa H 8. The process that comprises reacting A 3- 11chromium trioxide and recovering A -9,1141!-keto-21-hemisucclnoxypregenc.

WISE BARE'I'T.

REFERENCES CIT ED The following references are of record in the me ofthis patent:

Number Butenandt Dec. 9, 1941

